DESCRIPTION: CCK is a peptide hormone implicated in diverse biological functions ranging from post-prandial control of pancreatic enzyme secretion and gallbladder contraction to the modulation of centrally controlled behaviors such as feeding and anxiety. The applicant proposes a genetic Laurence J. Miller, M.D. Page approach to test the hypothesis that CCK serves an essential function in the intact animal. A strain of mice genetically incapable of producing CCK has been engineered by gene targeting mouse embryonic stem cells. This construct includes the bacterial lacZ reporter in a disrupted CCK gene copy. Heterozygous animals will be studied by histochemistry for B-galactosidase to explore the spatial and temporal patterns of CCK gene expression. Gene regions required for accurate expression will be defined by a series of deletion constructs in transgenic mice as well as a novel in vitro cell culture system using mouse ES cells. It is proposed that the physiologic function of CCK will be evaluated in a null mutant, CCKlacZ, and in a strain of obese mice produced elsewhere called FAT with a defect in carboxypeptidase E. Aim 2 focuses on feeding behavior including evaluations of meal size, duration, and microstructure of feeding. Neuropeptide Y (NPY) will also be explored in this aim. Aim 3 focuses on pancreatic enzyme secretion, including basal and stimulated activity, as well as potential adaptive responses. This work is felt to have implications for various disorders of gastrointestinal function, obesity, diabetes, and eating disorders.